Renin-angiotensin (RA) system is a hormone system being important to the maintenance of blood pressure or electrocyte balance in the living body, and plays an important role in the onset or exacerbation of circulatory system diseases such as hypertension, congestive heart failure, kidney damage, etc.
Renin, that is an important component of the RA system, is an aspartic protease secreted mainly from the kidney into the blood, and specifically decomposes angiotensinogen produced in the liver to produce angiotensin I. Angiotensin I is converted into angiotensin II by angiotensin-converting enzyme (ACE) being present at the lung or the vascular endothelial cells. Angiotensin II constricts the blood vessel as well as stimulates the adrenal gland to promote the secretion of aldosteron. Aldosteron acts on the kidney and let it pool sodium and excrete potassium. Such a cascade leads to the elevated blood pressure (Non-patent Document 1).
Recently, it is suggested that a component of the RA system exists locally in peripheral tissues such as heart, blood vessel, kidney, adrenal grand, adipose, etc. or the central tissues, and that a (pro)renin receptor may possibly play an important role as a novel component in the activation of the local RA system (Non-patent Document 2), and hence, the importance of the local (tissue) RA system is being recognized. It is suggested that the tissue RA system may possibly cause organ damages such as heart enlargement, arterioscrelosis, kidney damage, etc. by promoting in the long-term the remodeling of various organs such as heart, kidney, blood vessel, etc., while the circulatory RA system anticipates in the control of the short-term circulation (Non-patent Document 3).
As a medicament inhibiting the RA system, ACE inhibitors and angiotensin II receptor blockers (ARB) may be exemplified, and these medicaments (especially the former ones) have been proved to be useful as a remedy for the treatment of not only hypertension but also cardiovascular diseases and renal diseases such as heart failure, diabetic nephropathy, etc. and have been widely used in the clinical field (Non-patent Document 4, Non-patent Document 5).
Several steps for inhibiting the RA system exist, and among them, since renin is located on the most upper stream of the RA system and controls the rate of this cascade, it is theoretically quite appealing approach to inhibit renin (Non-patent Document 6, Non-patent Document 7). In fact, it has been confirmed that aliskiren, which is a renin inhibitor being developed recently, prominently inhibits the serum renin activity, and exhibits an excellent hypotensive activity as comparable to other RA system inhibitors in the clinical trial of hypertension patients (Non-patent Document 8, Non-patent Document 9, Non-patent Document 10).
Various renin inhibitors have been reported. For example, Patent Document 1 and Patent Document 2 reported that derivatives having a piperidine ring are useful as a renin inhibitor. Patent Document 3 reported that derivatives having a pyrrolidine ring are useful as a renin inhibitor. The compounds disclosed in these literatures are characteristic in that these compounds have a partial structure where a piperidine ring or a pyrrolidine ring binds to an amino group at the 3-position thereof via a carbonyl group or a methylene group. However, it has not been known until now that compounds having a basic structure of 3-(substituted-(benzoxazinon-6-yl)carbonylamino)piperidine, etc. are useful as a renin inhibitor.    [Non-patent Document 1] Nat Rev Drug Discov. 1(8): p. 621-36 (2002)    [Non-patent Document 2] Curr Hypertens Rep. 6(2): p. 129-32 (2004)    [Non-patent Document 3] Physiol. Rev. 86: p. 747-803 (2006)    [Non-patent Document 4] Curr Diab Rep. 6(1): p. 8-16 (2006)    [Non-patent Document 5] J Hypertens Suppl. 23(1): S9-17 (2005)    [Non-patent Document 6] J Exp Med. 106 (3): p. 439-53 (1957)    [Non-patent Document 7] J Am Soc Nephrol 16: p. 592-599 (2005)    [Non-patent Document 8] Hypertension 42 (6): p. 1137-43 (2003)    [Non-patent Document 9] Circulation 111 (8): p. 1012-8 (2005)    [Non-patent Document 10] J Hypertens. 24 (Suppl 4): S82. Abstract P4.269 (2006)    [Patent Document 1] WO 06/069788 pamphlet    [Patent Document 2] WO 06/094763 pamphlet    [Patent Document 3] WO 06/066896 pamphlet